Background/Purpose: Mucosal associated invariant T-cells (MAITs) are innate-like T lymphocytes that express a semi-invariant TCR repertoire that are activated by microbial ligands or cytokines including IL-23 and secrete inflammatory cytokines, including IL-17A. MAIT cells are enriched at mucosal surfaces and have been implicated in the pathogenesis of spondyloarthritis (SpA) and inflammatory bowel disease (IBD). Although the human enthesis is not a mucosal surface it is the primary site of inflammation in SpA which has strong association with IBD. The aim of this study was to investigate if a population of MAITs is present at the normal human enthesis thereby supporting the gut-enthesis axis concept. 

Methods: Healthy interspinous ligament and spinous process were harvested from patients undergoing elective surgery for the correction of mechanical spinal defects. Entheseal soft tissue (EST) and peri-entheseal bone (PEB) were separated, and cells were harvested by enzymatic and mechanical digestion respectively. The proportion of cells expressing markers consistent with MAITS (CD45+, CD3+, CD161+, TCRVα7.2+) were measured by flow cytometry in EST, PEB and matched blood. Expression of CD69 and CD45RA were examined for phenotypic analysis and IL-17A and TNF production was measured using intracellular flow following in vitro activation with PMA/ionomycin Transcript analysis for inflammatory, immunomodulatory and genes associated with tissue residency was performed on sorted entheseal MAITs and conventional CD8+ T-cells.

Results: As a proportion of total T-cells, MAITs were of approximately 3 fold and 2.5 fold greater abundance in EST and PEB respectively in comparison to matched peripheral blood (both p=0.034). MAITs in entheseal tissue had an overwhelming resident memory phenotype (CD69+, CD45RA-) median 53.2% (range 42.4 – 78.6%) in EST and 54.9% (45.2 – 82.1%) in PEB compared to those from blood 17.7 (6.8 – 69.4). They readily express IL-17A and TNF protein following PMA stimulation and showed higher basal expression of IL-23R (9-fold), RORC (3-fold), TNF (6-fold) and less TGFb (13-fold) and SOCS2 (5-fold). However, expression of transcripts relevant to tissue localisation was not altered in PEB MAITs compared to those from blood.

Conclusion: Healthy human entheseal tissue contains an enriched population of MAITs at a frequency comparable to that reported in the colon. The majority of these cells express a resident memory phenotype suggesting that they are a distinct population residing in entheseal tissue. These observations are potentially relevant to SpA pathogenesis, the observed link between SpA and IBD and may help to explain entheseal pathology following α4β7 integrin inhibition in patients with IBD since MAITs are known to express this integrin receptor.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-gut-enthesis-axis-coming-into-focus-with-the-description-of-enriched-entheseal-resident-mucosal-associated-invariant-t-cells-maits-capable-of-il17a-and-tnf-production/